Diagnostics & Imaging Week Contributing Writer

LONDON – The long haul towards identifying the genes that influence a woman's risk of inheriting breast cancer is continuing, with reports of additional genetic loci that alter breast cancer risk.

Two papers published in the March 29, 2009 issue of Nature Genetics detail the results of genome-wide association studies of huge numbers of women with breast cancer and controls. Each study reports the discovery of two new regions of the genome that alter a woman's risk of breast cancer.

Doug Easton, lead author of one of the papers and director of the Cancer Research UK Genetic Epidemiology Unit at the University of Cambridge, told Diagnostics & Imaging Week's sister publication, BioWorld International: "With these four new loci, we are now up to 13 loci altogether where common variants influence a woman's risk of breast cancer. Within the next three years, research teams around the world might well have discovered 20 or 30 loci in total, perhaps more – but there will come a point where the variants we are discovering will be rarer and rarer and have smaller and smaller effects on a woman's risk."

The title of the paper by Easton and his colleagues is: "Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2".

One of the loci discovered by the study funded by Cancer Research UK, which is on chromosome 3, increases breast cancer risk by about 12% in women who carry one faulty copy of the gene, and by 23% if they carry two faulty copies. By contrast, the other locus – on chromosome 17 – reduces risk by about 4% if the woman inherits one faulty copy, and by 11% if she inherits two faulty copies.

Easton said: "These two new genes bring us closer to developing a better test to identify women who are at a high risk of developing breast cancer, but there are still many more pieces of the genetic puzzle to find." Women with a strong family history of breast cancer are already being offered genetic screening by some clinics in the UK, he added. "Depending on the results, such women may well be offered regular screening from age 35 or 40, rather than from age 50 years as in the general population."

For this study, Easton and his collaborators scanned the entire genome of more than 400 women with breast cancer, to identify mutations or alterations that occurred more often in cancer patients than in healthy women. They then tested the most promising regions in more than 40,000 women with breast cancer, and 40,000 women without breast cancer, in an international collaboration involving more than 100 scientists from 16 countries.

One in five women in the general population are thought to carry two mutated copies of the genetic marker found on chromosome 3.

This susceptibility locus is close to two genes called NEK10 and SLC4A7. NEK10 belongs to a family of kinases that are involved in cell cycle control, some of which are known to be involved in regulation of mitosis. SLC4A7 encodes a protein that resides in the cell membrane and is known to be present in reduced amounts in breast cancer cells.

One in 14 women are thought to carry two mutated copies of the other genetic marker. One of the genes close to this susceptibility locus is called COX11; the protein it encodes is involved in mitochondrial respiratory metabolism and it is not clear how it could be related to breast cancer.

Easton said: "These two newly discovered susceptibility loci bring the fraction of the familial risk explained by all known common susceptibility alleles up from 5.4% before the current study, to 5.9%."

The true proportion of known susceptibility alleles is, however, already higher than 5.9%, as a further study reports another two new loci in the same issue of Nature Genetics. The title of this paper, by David Hunter of the Harvard School of Public Health in Boston, and collaborators is: "A multistage genome-wide association study in breast cancer identified two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)."

The first variant is on chromosome 1, in a region where little is known about the genes that reside there. The second variant is located within a gene on chromosome 14, which is involved in DNA repair. The name of this gene is RAD51L1.

Easton concluded: "Researchers in this field are already turning their attention to ways of identifying the rarer variants associated with increased risk of breast cancer. We are beginning to use newer methods of genome resequencing, in which large parts of the genomes of large numbers of people with a disease and of those without a disease, are completely resequenced, instead of just analyzing single nucleotide polymorphisms. These methods are still very expensive but they are very exciting."

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